The choice of a unique formulation, coupled with a prolonged polymerfree elution, maximizes DES efficacy. R. Byrne Deutsches Herzzentrum München

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1 The choice of a unique formulation, coupled with a prolonged polymerfree elution, maximizes DES efficacy R. Byrne Deutsches Herzzentrum München

2 Disclosures Lecture fees: B. Braun Melsungen, Biotronik, Boston Scientific Research grants to institution: Boston Scientific, Heartflow

3 Why -limus drugs are less effective in diabetics FACT #1: Direct Resistance of diabetic cells to limus drugs

4 Direct resistance of VSMCs to limus drugs 10 times higher -limus concentration is needed in the diabetic cell to achieve similar inhibition seen in non-diabetic cell! -limus target -limus target non-diabetic diabetic Normal patient Quiescent status: ERK NON ACTIVE mtor NON ACTIVE P27 HIGH CONCETRATION Normal patient Proliferative status: ERK ACTIVE mtor ACTIVE P27 LOW CONCENTRATION Diabetic patient Proliferative status: ERK HYPER ACTIVE mtor ACTIVE P27 VERY LOW CONCENTRATION

5 Why -limus drugs are less effective in diabetics FACT #2: Effect of other hormones

6 Diabetes and Overweight Overweight is a risk factor for diabetes and for CVD. Dietz W H, et al. NEJM. 1999; 341: % of diabetic patients (Type 2) are overweight or obese (Obesity Society Feb. 2015)

7 Leptin: Effects at vascular level Leptin is an hormone secreted by adipocytes (cells distributed ubiquitously throughout the body, also perivascularly, particularly in overweight patients) with specific vascular effects. Pathological status (Hyperleptinaemia) RESTENOSIS PERMANENT INFLAMMATORY STATUS PLAQUE PROGRESSION PRO-THROMBOTIC STATUS 9 times higher -olimus concentration is needed to block leptin-induced hyperplasia.

8 Why -limus drugs are less effective in diabetics Reasons for -limus drugs lower efficacy in diabetics: 1. Direct Resistance of diabetic cells to limus drugs 10 times higher -limus drug concentration is needed to achieve similar inhibition of non DM cells 2. Contribution of other hormones in limiting -limus action on cell proliferation 9 times higher -limus drug concentration is needed to stop Leptin-induced hyperplasia To improve PCI efficacy in diabetic patients we need to increase the «-limus» drug concentration inside the diabetic cells!

9 Unique technology for very high efficacy in diabetics: Amphilimus formulation

10 Amphilimus TM Formulation Sirolimus Fatty Acid R Immunosuppressant Anti-proliferative action Anti-microbial Inhibitor of inflammatory cell activities High potency Proprietary technology Sirolimus and Fatty Acid are eluted together Sustained drug elution timing Modulated drug bioavailability Raised homogeneous drug distribution Enhanced drug stability Combined effect

11 The key role of Fatty Acids in diabetes for ATP generation NON-Diabetic cell 70% DIABETIC cell 100% 30% FATTY ACID + SIROLIMUS Two pathways for ATP generation: 1. Glucose pathway (30%) 2. Fatty acid pathway (70%) Membrane protein overexpression leads to higher fatty acids bindings/ translocation. Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease - Glatz J; 2010 Physiol Rev 90:

12 Unique technology for very high efficacy in diabetics: Abluminal Reservoir Technology

13 Abluminal Reservoir Technology Alvimedica utilizes a proprietary polymer-free drug release system constituted by reservoirs on the stent's abluminal surface ARTERIAL WALL Drug elution is controlled and directed exclusively towards the vessel wall BLOOD FLOW No polymer No drug

14 Abluminal Reservoir Technology Abluminal Reservoir is the ONLY polymer-free technology able to provide the same elution kinetic obtained by the most effective polymeric DES. Effective elution profiles The Reservoir shape defines drug release kinetic (Fick law) Peak drug tissue concentration during the first days 50% drug elution in approximately 18 days 65%-70% drug elution within 30 days Complete drug elution within 90 days

15 % Eluted % Eluted Abluminal Reservoir Technology Abluminal Reservoirs, contrary to polymers, allow a mix of substances to be simultaneously eluted for a maximized synergetic effect Polymers Abluminal Reservoir POLYMERIC MATRIX Polymers act as a filter (porosity) determining which molecules are very fast released (small ones) and those slowly released (big ones) Abluminal Reservoir allows different substances to be simultaneously eluted - the kinetic release is fixed by the reservoir shape. Fast elution Small molecule Big molecule Slow elution Small molecule Slow elution Big molecule Time Time

16 Can drug distribution be further optimized to maximize DES efficacy? Cre8 EVO: New Stent Architecture (EvenArt)

17 New Stent Architecture for maximized efficacy (EvenArt) An innovative stent architecture has been developed to improve even more the homogeneous drug distribution within the vessel wall, in particular in case of complex coronary anatomies and pathologies like those of diabetic patients New stent architecture

18 #1: Cre8 TM EVO - New Stent Architecture (EvenArt) Shortened pitch with reduced crown width and different link number/ pattern enhance Elution Profile in challenging anatomies/ conditions Shortened pitch

19 DRUG/EFFICACY matrix Geometrical Solution Reserviors closer to each others Cre8 TM Cre8 TM EVO - EvenArt Pharmaceutical Solution Amphilimus TM formulation

20 #2: Cre8 TM EVO - New Stent Architecture (EvenArt) and delivery system for better Deliverability/ Conformability Vessel features in diabetic patients Cre8 TM EVO new stent architecture, coupled with enhanced delivery system, allows for excellent device Deliverability and Conformability in any anatomy; even in the most challenging patients/ settings (diabetics)

21 DIAMETERS [mm] Cre8 TM EVO - Features summary DES features Polymer-free DES Reservoir Technology Amphilimus Formulation (Sirolimus 0,9 + FA) EvenArt stent architecture µg mm 2 Bio Inducer Surface (pure Carbon surface) Zero stent shortening upon expansion 2 Platinum stent ends Co-Cr thin stent strut: 70/80 µm Delivery System features Balanced and hydrophilic coated shaft Short balloon tapers RBP = 18atm for the entire product catalogue (from 2.25 to 4.5mm) NOMINAL LENGTHS [mm] ,25 x x x x x x x 2,50 x x x x x x x x 2,75 x x x x x x x x 3,00 x x x x x x x x 3,50 x x x x x x x x 4,00 x x x x x x 4,50 x x x x x

22 Conclusions Reasons for lower DES efficacy in diabetics: VSMCs of diabetic patients are less responsive to limus drugs. High blood levels of the hormone leptin, which stimulates VSMCs proliferation, are often present in diabetic and overweight patients. A prolonged elution of the Amphilimus TM formulation from Abluminal Reservoirs, allows for higher limus drug concentration to re-establish VSMCs inhibition and prevent in-stent restenosis. Cre8 TM EVO, with its new stent architecture and delivery system, can: Further advance DES efficacy specifically in complex anatomies/ patients (diabetics). Provide excellent device Deliverability and Conformability

23 Thank you for your attention! Robert A. Byrne MB BCh PhD FESC